1. Field of the Invention
The present invention relates to preparation methods of rhenium complexes, and more specifically, to a method of preparing a rhenium complex by use of a borohydride exchange resin.
2. Description of the Related Art
In general, rhenium having isotopes of rhenium-186 (186Re) and rhenium-188 (188Re) belongs to the same group on the periodic table, together with technetium, and functions as a beta emitter for therapy and a gamma emitter for imaging at the same time. Practically, rhenium-186 or rhenium-188 has been utilized as radioactive pharmaceuticals applicable for palliating bone pain caused by secondary bone metastasis of prostatic cancer, lung cancer, breast cancer or the like.
Preparation methods of rhenium complex useful as radioactive pharmaceuticals include the formation of a rhenium-ligand complex, and then the labeling of a target compound through ligand substitution reaction.
Specifically, the rhenium complex results from the reaction of perrhenic acid with a reducing agent at a low pH, to obtain reduced rhenium, which then reacts with a ligand at high temperatures.
In this regard, S. Prakash et al. discloses that NH4ReO4 is mixed with aqueous ethylenediamine solution and SnCl2·2H2O, and then heated for 30 min in a nitrogen atmosphere to prepare a desired rhenium complex [S. Prakash et al., Nuclear Medicine & Biology, Vol. 23, pp543-549, 1996].
Further, Jeong Jae-Min et al. discloses that 188Re-perrhenate eluate is added to a vial containing 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanedithiol (TDD), SnCl2·2H2O and tartaric acid, and then boiled for 30 min, to obtain Re-TDD complex (J. M. Jeong et al., Nuclear Medicine & Biology, Vol 28, pp197-204, 2001].
Furthermore, S. Guhlke et al. discloses that 188Re-perrhenate eluate is added to a vial containing Bz-MAG3-DH-Boc solution, K,Na-tartrate solution, SnCl2·2H2O and hydrochloric acid, pH about 3.8, after which a heating process is performed at 90° C. for 1 hour, to obtain 188Re-MAG3-DH-Boc complex [S. Guhlke et al., Nuclear Medicine & Biology, Vol 25, pp621-631, 1998].
Like these, as for the formation of the complex through reaction of perrhenic acid with the ligand, the reduction of rhenium using the reducing agent should be preceded.
In such cases, the reduction is carried out by means of electrolysis or using the reducing agent, such as stannous chloride dehydrate (SnCl2·2H2O), ferrous ion, ferrous-ascobate, formamidinesulfinic acid, sodium borohydride, etc. In common, use of stannous chloride dehydrate is preferable.
Although being stable under acidic conditions, stannous chloride dehydrate forms a precipitate under basic conditions. Whereas, sodium borohydride is stable under basic conditions, however becomes unstable under acidic conditions. Further, excessive use of the above reducing agent in the form of aqueous solution leads to the production of impurities, such as colloids, and residual toxicity. Thus, limitations are imposed on the use of predetermined amounts or more of the above reducing agent.
Moreover, in the above preparations, heat treatment should be performed to reduce rhenium or to react the reduced rhenium with the ligand. In this case, the heat treatment is carried out under nitrogen atmosphere to maintain a reduction atmosphere. However, such a high temperature reaction may cause the deterioration of antibodies and proteins bonded to the ligand, and also, may cleave chemical bonds. Therefore, antibodies and proteins weak against heat cannot be used. In addition, manufacturers have difficulties in controlling conditions of a refluxing process for use in treatment of radioactive materials at high temperatures.